U.S. patent application number 16/637502 was filed with the patent office on 2020-08-13 for pharmaceuticals and dosing means for human aging reversal.
The applicant listed for this patent is INTERVENE IMMUNE, INC.. Invention is credited to Robert T. Brooke, Gregory M. Fahy.
Application Number | 20200254066 16/637502 |
Document ID | 20200254066 / US20200254066 |
Family ID | 1000004786320 |
Filed Date | 2020-08-13 |
Patent Application | download [pdf] |
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United States Patent
Application |
20200254066 |
Kind Code |
A1 |
Fahy; Gregory M. ; et
al. |
August 13, 2020 |
PHARMACEUTICALS AND DOSING MEANS FOR HUMAN AGING REVERSAL
Abstract
A combination of medications and medication doses is disclosed
whereby age-related changes in systemic inflammation, cancer risk,
heart disease risk, CD38 expression, hair color, thymotrophic
hormones, immune cell populations, the CD4/CD8 cell ratio, bone
marrow density, thymus structure, kidney function, and epigenetic
age can be reversed in humans. Surprisingly, agents that accelerate
the growth of cells reduce cancer risk, agents that intensify
immune responses attenuate age-related inflammation, agents with no
prior connection to hair color reverse age-related hair whitening,
and a combination of agents that induces IGF-1, a hormone
previously thought to drive systemic aging, results in a reversal
of systemic aging as documented by an epigenetic clock. Medication
combinations useful in the present invention include human growth
hormone (GH) or GH releasers, dehydroepiandrosterone (DHEA), and
metformin.
Inventors: |
Fahy; Gregory M.; (Norco,
CA) ; Brooke; Robert T.; (Manhattan Beach,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INTERVENE IMMUNE, INC. |
Manhattan Beach |
CA |
US |
|
|
Family ID: |
1000004786320 |
Appl. No.: |
16/637502 |
Filed: |
August 7, 2018 |
PCT Filed: |
August 7, 2018 |
PCT NO: |
PCT/US2018/045684 |
371 Date: |
February 7, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 38/27 20130101;
A61K 31/5685 20130101 |
International
Class: |
A61K 38/27 20060101
A61K038/27; A61K 31/5685 20060101 A61K031/5685 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 9, 2017 |
US |
62543269 |
Claims
1. The use of a combination of human growth hormone (GH) and/or a
GH releaser, dehydroepiandrosterone (DHEA), and metformin to
manufacture a pharmaceutical dosage form to treat, prevent, or
reverse broad aspects of human aging, including any one of, any
combination of, or all of age-related changes in systemic
inflammation as indicated by hsCRP or other accepted markers,
cancer risk as indicated by PSA levels or the percent of free PSA
or the ratio of PSA to percent of free PSA or its reciprocal and/or
by the lymphocyte to monocyte cell ratio, heart disease risk as
indicated by the lymphocyte to monocyte cell ratio, CD38-positive
blood cell counts or percentages, hair color, IL-7 levels, IL-21
levels, the CD4/CD8 cell ratio, naive CD4 and/or CD8 cell numbers
or percentages, total CD4 and/or CD8 T cell numbers or percentages,
bone marrow density, thymic fat-free fraction, glomerular
filtration, and epigenetic age, as well as to reduce or prevent
GH-induced or GH releaser-induced hyperinsulinemia.
2. The pharmaceutical dosage form of claim 1, which may comprise
any of a) three separate agents or agent classes (the GH and/or GH
releaser; DHEA; and metformin), which are to be administered
simultaneously or within 2 hours of one another; b) GH and/or a GH
releaser used simultaneously with or within two hours of a unified
companion product composition containing DHEA in combination with
metformin.
3. A composition for use in the treatment of human aging,
comprising a combination of GH and/or a GH releaser,
dehydroepiandrosterone, and metformin whose administration results
in mitigation of age-related changes in any one of, any combination
of, or all of the following: systemic inflammation as indicated by
hsCRP or other accepted markers, cancer risk as indicated by PSA
levels or the percent of free PSA or the ratio of PSA to percent of
free PSA or its reciprocal and/or by the lymphocyte to monocyte
cell ratio, heart disease risk as indicated by the lymphocyte to
monocyte cell ratio, CD38-positive blood cell counts or
percentages, hair color, IL-7 levels, IL-21 levels, the CD4/CD8
cell ratio, naive CD4 and/or CD8 cell numbers or percentages, total
CD4 and/or CD8 T cell numbers or percentages, bone marrow density,
thymic fat-free fraction, glomerular filtration, and epigenetic
age, as well as to reduce or prevent GH-induced or GH
releaser-induced hyperinsulinemia.
4. The composition of claim 3, which may comprise any of: a) three
separate agents or agent classes (the GH and/or GH releaser; DHEA;
and metformin), which are to be administered simultaneously or
within 2 hours of one another, or b) GH and/or a GH releaser used
simultaneously with or within two hours of a unified companion
product composition containing DHEA in combination with
metformin.
5. A method for the mitigation or reversal of human aging,
comprising administering a combination of GH and/or a GH releaser,
dehydroepiandrosterone, and metformin so as to result in mitigation
or reversal of age-related changes in any one of, any combination
of, or all of the following: systemic inflammation as indicated by
hsCRP or other accepted markers, cancer risk as indicated by PSA
levels or the percent of free PSA or the ratio of PSA to percent of
free PSA or its reciprocal and/or by the lymphocyte to monocyte
cell ratio, heart disease risk as indicated by the lymphocyte to
monocyte cell ratio, CD38-positive blood cell counts or
percentages, hair color, IL-7 levels, IL-21 levels, the CD4/CD8
cell ratio, naive CD4 and/or CD8 cell numbers or percentages, total
CD4 and/or CD8 T cell numbers or percentages, bone marrow density,
thymic fat-free fraction, glomerular filtration, and epigenetic
age, as well as to reduce or prevent GH-induced of GH
releaser-induced hyperinsulinemia.
6. The method of claim 5, which may comprise any of: a)
administering three separate agents or agent classes (the GH and/or
GH releaser; DHEA; and metformin) simultaneously or within 2 hours
of one another, or b) administering GH and/or a GH releaser
simultaneously with or within two hours of the oral administration
of a unified companion product composition containing DHEA in
combination with metformin.
7. A composition for use in the treatment of human aging,
comprising an agent that increases IGF-1 levels and one or more
insulin-lowering agents whose administration results in mitigation
of age-related changes in any one of, any combination of, or all of
the following: immune system function as indicated by the
lymphocyte to monocyte ratio, CD38-positive blood cell counts or
percentages, total CD4 and/or CD8 T cell numbers or percentages,
IL-7 levels, IL-21 levels, the CD4/CD8 cell ratio, naive CD4 and/or
CD8 cell numbers or percentages, bone marrow density, thymic
density or fat-free fraction, or other accepted markers of immune
system function, inflammation as indicated by hsCRP or other
accepted markers, cancer risk as indicated by PSA levels, the
percent of free PSA, the ratio of PSA to percent of free PSA, its
reciprocal, and/or by the lymphocyte to monocyte cell ratio or
other accepted markers of cancer risk, heart disease risk as
indicated by the lymphocyte to monocyte cell ratio, CD38-positive
blood cell counts or percentages or other accepted markers of heart
disease risk, hair color, glomerular filtration or other accepted
markers of kidney function, epigenetic age, or other critical
endpoints of aging, as well as to reduce or prevent GH-induced or
GH releaser-induced hyperinsulinemia.
8. A composition for use in the treatment of human aging,
comprising a combination of one or more anabolic agents with one or
more insulin-lowering agents whose administration results in
mitigation of age-related changes in any one of, any combination
of, or all of the following: immune system function as indicated by
the lymphocyte to monocyte ratio, CD38-positive blood cell counts
or percentages, total CD4 and/or CD8 T cell numbers or percentages,
IL-7 levels, IL-21 levels, the CD4/CD8 cell ratio, naive CD4 and/or
CD8 cell numbers or percentages, bone marrow density, thymic
density or fat-free fraction, or other accepted markers of immune
system function, inflammation as indicated by hsCRP or other
accepted markers, cancer risk as indicated by PSA levels, the
percent of free PSA, the ratio of PSA to percent of free PSA, its
reciprocal, and/or by the lymphocyte to monocyte cell ratio or
other accepted markers of cancer risk, heart disease risk as
indicated by the lymphocyte to monocyte cell ratio, CD38-positive
blood cell counts or percentages or other accepted markers of heart
disease risk, hair color, glomerular filtration or other accepted
markers of kidney function, epigenetic age, or other critical
endpoints of aging as well as to reduce or prevent GH-induced or GH
releaser-induced hyperinsulinemia.
Description
[0001] This patent application claims priority to U.S. Provisional
Application Ser. No. 62/543,269, filed on Aug. 9, 2017, and is also
related to U.S. patent application Ser. No. 14/997,397 ("Novel
Applications of Growth Hormone Therapy and Related Pharmaceutical
Compositions"). It is additionally related to U.S. Pat. No.
6,297,212 B1 ("Growth Hormone Therapy and Related Methods and
Pharmaceutical Compositions") and U.S. Pat. No. 7,166,569 B2
("Method for the Prevention of Transplant Rejection"). All of the
foregoing applications and patents are herein expressly
incorporated by reference, in their entirety.
BACKGROUND OF THE INVENTION
[0002] The present invention was initially motivated by the
desirability of discovering medications and medication doses and
methods capable of advantageously regenerating the human thymus
(i.e., pharmacologically addressing the medical condition known as
thymic involution) so as to prevent age-related immune dysfunction
(immunosenescence) or restore immune function (reverse
immunosenescence) in the elderly. We sought to correct the
deficiencies of the few [12, 33, 34] prior art medications and
medication doses and methods for human thymus regeneration, which
have failed to adequately address the issue of insulin control,
safety, and efficacy in otherwise healthy aging adults. Prior to
the present invention, the following concerns and unanswered
questions confronted the use of prior art medications and
medication doses and methods intended to treat the medical
condition known as thymic involution (i.e., to induce clinical
thymus regeneration).
[0003] The Problem with Growth Hormone: Aging, Diabetes, and
Cancer
[0004] Growth hormone (GH) has been the basis of attempted human
thymus regeneration to date [12, 33, 34] based in part on positive
short-term results in animals [25]. However, there is no approved
or generally recognized benefit of GH other than to treat certain
childhood diseases and failure to grow, or bona fide GH
deficiencies in adults, which are quite rare. In addition, the
scientific consensus is that aging itself is driven by the IGF-1
produced in response to GH secretion given the universality of the
involvement of similar signaling processes in the aging of most
animal species [28, 29, 43], the fact that mutant mice deficient in
GH/IGF1 signaling live longer than wild-type mice [7, 19, 29, 41,
43] and that there is an inverse correlation between IGF-1 levels
and lifespans between mouse strains [48].
[0005] One pro-aging effect of HGH administration is the
"diabetogenic" effect of GH, wherein HGH increases insulin
resistance and consequently increases blood insulin levels [30,
38]. Elevated insulin levels may lead to an increased risk of
atherosclerosis, other cardiovascular diseases, and accelerated
aging in general [31]. An instructive hallmark of calorie
restriction, which is one of the most powerful anti-aging
interventions now known, is simultaneous reduction in both glucose
and insulin levels secondary to powerfully increased insulin
sensitivity [4, 45]. Normal aging and GH administration both result
in the opposite effect, i.e., elevated insulin and unchanged or
elevated glucose levels, owing to increased insulin resistance.
This phenomenon is often called metabolic syndrome or type II
diabetes, and is responsible for many age-related diseases. It is
undesirable to foster this condition in an attempt to slow aging,
but this serious side effect of HGH administration has been almost
universally ignored. Although Fahy, uniquely, proposed HGH
administration in combination with dehydroepiandrosterone (DHEA) to
block the diabetogenic effect of HGH [11, 12], his method was only
shown to be effective in a single relatively young individual [12,
13], and its validity and sufficiency for the general population
therefore remains unknown. Recently, 50 mg of DHEA per day was
found to improve glucose tolerance in 65-75 year old men [46], but
this was in the absence of GH administration, leaving the
effectiveness of DHEA in combination with GH as well as optimal
methods of DHEA use with GH unresolved. Past use of GH for thymus
regeneration in HIV patients (who may be unrepresentative of the
general healthy aging population [32]) ignored the issue of
hyperinsulinemia [33, 34], and it is unknown whether correcting
hyperinsulinemia might prevent any benefit of thymus
regeneration.
[0006] GH administration to adult humans [1, 3, 18, 42] and to
adult rodents [10, 23, 26] has not been shown to increase the risk
of developing cancer despite often elevating IGF-1 levels to far
above the normal range. However, paradoxically, the highest levels
of IGF-1 in men not treated with HGH have been associated with
about a 50% increase in prostate cancer risk [36], and in women,
IGF-1 stimulates processes that worsen breast cancer outcomes [9].
Therefore, there has been an unresolved concern that use of growth
hormone for thymus regeneration may lead to significant elevations
in cancer risk. Moreover, DHEA is a precursor to testosterone, and
androgens are a risk factor for prostate cancer development and
progression [39]. Therefore, the combination of DHEA and HGH is
particularly concerning from the standpoint of potential
exacerbation of prostate cancer, and it might be argued that the
decline of DHEA with age [40, 44], like the decline of GH secretion
and IGF-1 levels with age, has arisen as a hedge against cancer.
Furthermore, sex hormones, including androgens, have been shown to
drive thymus involution [16, 17], making the use of DHEA in a
treatment for thymus regeneration potentially
counterproductive.
[0007] Thymus Regeneration Vs "Inflammaging"
[0008] In addition to increased insulin resistance, another major
hallmark of aging is "inflammaging" [14], which is a state of
chronic and generalized inflammation that arises in the course of
normal aging and has been speculated to contribute to age-related
increases in cancer risk. It is logical to assume that if thymus
regeneration were to increase the intensity of immune responses in
the elderly, this would exacerbate inflammaging, and in fact, one
famed gerontologist and immunologist to whom thymus regeneration
was suggested by one of the present inventors (G. M.F.) did
strongly express just this concern. A priori, there is no way to
rebut this concern or determine the magnitude of this presumed
problem, and the prior art is completely silent on this question;
although HGH has been widely used, its potential exacerbation of
inflammaging has not been defined. To underscore the seriousness of
this potential drawback, it was recently reported that a new immune
system stimulating drug, TGN-1412, induced a severe inflammatory
reaction known as a "cytokine storm" in a Phase 1 trial, and
therefore had to have its development halted [6]. Furthermore, the
thymus involutes early in life in all vertebrates, including
humans, leading some researchers to question if this change is
adaptive, perhaps, for example, to blunt inflammation later in
life. If so, thymus regeneration could be counterproductive.
[0009] In order to address these unknowns, a first of its kind
one-year clinical trial was carried out on 9 healthy men aged
50-65. The results have been illuminating, not only with respect to
the above-described questions, but also as to the existence of
previously unknown deficiencies of prior art methods as well as the
effectiveness of a new pharmaceutical dosage form that provides an
unprecedented set of new health benefits and valuable new drug
indications. These indications go beyond the immediate goals of
thymus regeneration and T cell improvement. The same essential
pharmacological approach should be effective as well in women.
SUMMARY OF THE INVENTION
[0010] The invention is a drug combination and mode of drug
administration that has novel therapeutic effects that are
consistent with a generalized reversal of human aging. The
invention is also the first demonstrated method for reversing
multiple aspects of aging, and even aging in general, in humans.
More specifically, the invention consists of a combination of human
growth hormone (GH) and/or GH releasers, dehydroepiandrosterone
(DHEA), and metformin and means of delivering this combination of
medications that results in the reversal of normal age-related
changes in kidney function, systemic inflammation, cancer risk,
heart disease risk, CD38 expression, hair color, thymotrophic
hormones, the CD4/CD8 cell ratio, immune cell populations, bone
marrow density, thymus structure, and epigenetic age. Still more
specifically, the above drug combination is to be given so as to
optimize the CD4/CD8 cell ratio, which, using prior art methods,
cannot be correctly optimized. Still more specifically, the above
drug combination is to be given so as to minimize GH-induced or GH
releaser-induced hyperinsulinemia and unpleasant side effects.
[0011] The invention also comprises the use of a combination of
human growth hormone (GH) and/or GH releasers with
dehydroepiandrosterone (DHEA) and metformin to manufacture a
pharmaceutical dosage form to treat or to prevent broad aspects of
human aging, including any one of, any combination of, or all of
age-related changes in systemic inflammation as indicated by hsCRP
or other accepted markers, cancer risk as indicated by PSA levels
or the percent of free PSA or the ratio of PSA to percent of free
PSA or its reciprocal and/or by the lymphocyte to monocyte cell
ratio, heart disease risk as indicated by the lymphocyte to
monocyte cell ratio, CD38-positive blood cell counts or
percentages, hair color, IL-7 levels, IL-21 levels, the CD4/CD8
cell ratio, naive CD4 and/or CD8 cell numbers or percentages, total
CD4 and/or CD8 T cell numbers or percentages, bone marrow density,
thymic fat-free fraction, glomerular filtration, and epigenetic
age, as well as to reduce or prevent GH-induced hyperinsulinemia.
The pharmaceutical dosage form or composition may consist of three
separate agents or agent classes (the GH and/or GH releaser; DHEA;
and metformin) administered simultaneously or within 2 hours of one
another, or it may consist of GH and/or a GH releaser used
simultaneously with or within two hours of a unified companion
product composition containing DHEA in combination with
metformin.
[0012] More particularly, in one aspect of the invention there is
disclosed the use of a combination of human growth hormone (GH)
and/or a GH releaser, dehydroepiandrosterone (DHEA), and metformin
to manufacture a pharmaceutical dosage form to treat, prevent, or
reverse broad aspects of human aging, including any one of, any
combination of, or all of age-related changes in systemic
inflammation as indicated by hsCRP or other accepted markers,
cancer risk as indicated by PSA levels or the percent of free PSA
or the ratio of PSA to percent of free PSA or its reciprocal and/or
by the lymphocyte to monocyte cell ratio, heart disease risk as
indicated by the lymphocyte to monocyte cell ratio, CD38-positive
blood cell counts or percentages, hair color, IL-7 levels, IL-21
levels, the CD4/CD8 cell ratio, naive CD4 and/or CD8 cell numbers
or percentages, total CD4 and/or CD8 T cell numbers or percentages,
bone marrow density, thymic fat-free fraction, glomerular
filtration, and epigenetic age, as well as to reduce or prevent
GH-induced or GH releaser-induced hyperinsulinemia. This
combination may comprise any of a) three separate agents or agent
classes (the GH and/or GH releaser; DHEA; and metformin), which are
to be administered simultaneously or within 2 hours of one another;
and b) GH and/or a GH releaser used simultaneously with or within
two hours of a unified companion product composition containing
DHEA in combination with metformin.
[0013] In another aspect of the invention, there is disclosed a
composition for use in the treatment of human aging, comprising a
combination of GH and/or a GH releaser, dehydroepiandrosterone, and
metformin whose administration results in mitigation of age-related
changes in any one of, any combination of, or all of the following:
systemic inflammation as indicated by hsCRP or other accepted
markers, cancer risk as indicated by PSA levels or the percent of
free PSA or the ratio of PSA to percent of free PSA or its
reciprocal and/or by the lymphocyte to monocyte cell ratio, heart
disease risk as indicated by the lymphocyte to monocyte cell ratio,
CD38-positive blood cell counts or percentages, hair color, IL-7
levels, IL-21 levels, the CD4/CD8 cell ratio, naive CD4 and/or CD8
cell numbers or percentages, total CD4 and/or CD8 T cell numbers or
percentages, bone marrow density, thymic fat-free fraction,
glomerular filtration, and epigenetic age, as well as to reduce or
prevent GH-induced or GH releaser-induced hyperinsulinemia. This
composition may comprise any of a) three separate agents or agent
classes (the GH and/or GH releaser; DHEA; and metformin), which are
to be administered simultaneously or within 2 hours of one another,
or b) GH and/or a GH releaser used simultaneously with or within
two hours of a unified companion product composition containing
DHEA in combination with metformin.
[0014] In still another aspect of the invention, there is disclosed
a method for the mitigation or reversal of human aging, comprising
administering a combination of GH and/or a GH releaser,
dehydroepiandrosterone, and metformin so as to result in mitigation
or reversal of age-related changes in any one of, any combination
of, or all of the following: systemic inflammation as indicated by
hsCRP or other accepted markers, cancer risk as indicated by PSA
levels or the percent of free PSA or the ratio of PSA to percent of
free PSA or its reciprocal and/or by the lymphocyte to monocyte
cell ratio, heart disease risk as indicated by the lymphocyte to
monocyte cell ratio, CD38-positive blood cell counts or
percentages, hair color, IL-7 levels, IL-21 levels, the CD4/CD8
cell ratio, naive CD4 and/or CD8 cell numbers or percentages, total
CD4 and/or CD8 T cell numbers or percentages, bone marrow density,
thymic fat-free fraction, glomerular filtration, and epigenetic
age, as well as to reduce or prevent GH-induced of GH
releaser-induced hyperinsulinemia. This method may further comprise
any of:
[0015] a) administering three separate agents or agent classes (the
GH and/or GH releaser; DHEA; and metformin) simultaneously or
within 2 hours of one another, or b) administering GH and/or a GH
releaser simultaneously with or within two hours of the oral
administration of a unified companion product composition
containing DHEA in combination with metformin.
[0016] In still another aspect of the invention, there is disclosed
a composition for use in the treatment of human aging, comprising
an agent that increases IGF-1 levels and one or more
insulin-lowering agents whose administration results in mitigation
of age-related changes in any one of, any combination of, or all of
the following: immune system function as indicated by the
lymphocyte to monocyte ratio, CD38-positive blood cell counts or
percentages, total CD4 and/or CD8 T cell numbers or percentages,
IL-7 levels, IL-21 levels, the CD4/CD8 cell ratio, naive CD4 and/or
CD8 cell numbers or percentages, bone marrow density, thymic
density or fat-free fraction, or other accepted markers of immune
system function, inflammation as indicated by hsCRP or other
accepted markers, cancer risk as indicated by PSA levels, the
percent of free PSA, the ratio of PSA to percent of free PSA, its
reciprocal, and/or by the lymphocyte to monocyte cell ratio or
other accepted markers of cancer risk, heart disease risk as
indicated by the lymphocyte to monocyte cell ratio, CD38-positive
blood cell counts or percentages or other accepted markers of heart
disease risk, hair color, glomerular filtration or other accepted
markers of kidney function, epigenetic age, or other critical
endpoints of aging, as well as to reduce or prevent GH-induced or
GH releaser-induced hyperinsulinemia.
[0017] Yet another aspect of the invention involves a composition
for use in the treatment of human aging, comprising a combination
of one or more anabolic agents with one or more insulin-lowering
agents whose administration results in mitigation of age-related
changes in any one of, any combination of, or all of the following:
immune system function as indicated by the lymphocyte to monocyte
ratio, CD38-positive blood cell counts or percentages, total CD4
and/or CD8 T cell numbers or percentages, IL-7 levels, IL-21
levels, the CD4/CD8 cell ratio, naive CD4 and/or CD8 cell numbers
or percentages, bone marrow density, thymic density or fat-free
fraction, or other accepted markers of immune system function,
inflammation as indicated by hsCRP or other accepted markers,
cancer risk as indicated by PSA levels, the percent of free PSA,
the ratio of PSA to percent of free PSA, its reciprocal, and/or by
the lymphocyte to monocyte cell ratio or other accepted markers of
cancer risk, heart disease risk as indicated by the lymphocyte to
monocyte cell ratio, CD38-positive blood cell counts or percentages
or other accepted markers of heart disease risk, hair color,
glomerular filtration or other accepted markers of kidney function,
epigenetic age, or other critical endpoints of aging as well as to
reduce or prevent GH-induced or GH releaser-induced
hyperinsulinemia.
BRIEF DESCRIPTION OF THE FIGURES
[0018] FIG. 1 provides evidence that the invention surprisingly
reverses age-related inflammation ("inflammaging") based on reduced
levels of the inflammatory marker, C-reactive protein (CRP) over
time.
[0019] FIG. 2 provides evidence that the invention surprisingly
reverses the age-related increase in prostate cancer risk based on
reduced levels of prostate-specific antigen (PSA), increased
percentages of free (unbound) PSA, and the ratio of PSA to free
PSA.
[0020] FIG. 3 provides evidence that the invention surprisingly
reverses one of the most central drivers of aging in mammals,
namely, the normal age-related reduction in cellular NAD levels,
based on a reduced ratio of CD38-positive monocytes to lymphocytes.
The same finding indicates substantially reduced general risk of
cancer and cardiovascular disease.
[0021] FIG. 4 shows that the lymphocyte to monocyte ratio, which
increases as cancer and cardiovascular disease risks decrease,
increases in proportion to the replacement of thymic fat with
putatively functional thymic mass.
[0022] FIG. 5 provides evidence that the invention surprisingly
reverses the aging of hair follicles, based on increased hair
pigmentation over the course of treatment.
[0023] FIG. 6 provides evidence that the invention surprisingly
restores thymotrophic hormones in a subset of aging men, based on
correlated increases in both IL-7 and FGF-21 in these men.
[0024] FIG. 7 reveals a previously unknown phenomenon, i.e., that
the CD4/CD8 cell ratio peaks in the face of a constant or an
increasing dose of GH or rise in IGF-1, which enables a novel GH
dosing regimen that can prevent the decline in CD4/CD8 ratio over
time.
[0025] FIG. 8 provides the first evidence that the invention can
reverse thymic involution in all men with normal age-related thymic
involution, based on measurement of increased thymic fat-free
fraction (TFFF).
[0026] FIG. 9 provides evidence that the invention successfully
improves T cell populations in a subset of aging men and that the
subset of men who benefit can be predicted prior to treatment.
[0027] FIG. 10 provides evidence that the invention reverses renal
functional aging based on improving glomerular filtration over
time.
[0028] FIG. 11 provides the first evidence that, surprisingly, the
invention can reverse generalized aging, based on reduced
biological age after treatment as measured by a well-accepted
epigenetic aging clock.
[0029] FIG. 12 demonstrates that the invention can successfully
suppress GH-induced hyperinsulinemia despite the increasing GH
doses described in FIG. 1.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The invention consists of the use of a combination of human
growth hormone (GH) and/or a GH releaser, dehydroepiandrosterone
(DHEA), and metformin to manufacture a pharmaceutical dosage form
to treat, prevent, or reverse broad aspects of human aging,
including any one of, any combination of, or all of age-related
changes in systemic inflammation as indicated by CRP or other
accepted markers, cancer risk as indicated by PSA levels or the
percent of free PSA or the ratio of PSA to percent of free PSA or
its reciprocal and/or by the lymphocyte to monocyte cell ratio,
heart disease risk as indicated by the lymphocyte to monocyte cell
ratio, CD38-positive blood cell counts or percentages, hair color,
IL-7 levels, IL-21 levels, the CD4/CD8 cell ratio, naive CD4 and/or
CD8 cell numbers or percentages, total CD4 and/or CD8 T cell
numbers or percentages, bone marrow density, thymic fat-free
fraction, glomerular filtration, and epigenetic age, as well as to
reduce or prevent GH-induced or GH releaser-induced
hyperinsulinemia. The pharmaceutical dosage form or composition may
consist of three separate agents or agent classes (the GH and/or GH
releaser; DHEA; and metformin) administered simultaneously or
within 2 hours of one another, or it may consist of GH and/or a GH
releaser used simultaneously with or within two hours of a unified
companion product composition containing DHEA in combination with
metformin.
[0031] The invention is also a composition for use in the treatment
of human aging, comprising a combination of GH and/or a GH
releaser, dehydroepiandrosterone, and metformin whose
administration results in mitigation of age-related changes in any
one of, any combination of, or all of the following: systemic
inflammation as indicated by CRP or other accepted markers, cancer
risk as indicated by PSA levels or the percent of free PSA or the
ratio of PSA to percent of free PSA or its reciprocal and/or by the
lymphocyte to monocyte cell ratio, heart disease risk as indicated
by the lymphocyte to monocyte cell ratio, CD38-positive blood cell
counts or percentages, hair color, IL-7 levels, IL-21 levels, the
CD4/CD8 cell ratio, naive CD4 and/or CD8 cell numbers or
percentages, total CD4 and/or CD8 T cell numbers or percentages,
bone marrow density, thymic fat-free fraction, glomerular
filtration, and epigenetic age, as well as to reduce or prevent
GH-induced or GH releaser-induced hyperinsulinemia. The composition
may consist of three separate agents or agent classes (the GH
and/or GH releaser; DHEA; and metformin) administered
simultaneously or within 2 hours of one another, or it may consist
of GH and/or a GH releaser used simultaneously with or within two
hours of a unified companion product composition containing DHEA in
combination with metformin.
[0032] The invention is also a method for the mitigation or
reversal of human aging, comprising administering a combination of
GH and/or a GH releaser, dehydroepiandrosterone, and metformin so
as to result in mitigation or reversal of age-related changes in
any one of, any combination of, or all of the following: systemic
inflammation as indicated by CRP or other accepted markers, cancer
risk as indicated by PSA levels or the percent of free PSA or the
ratio of PSA to percent of free PSA or its reciprocal and/or by the
lymphocyte to monocyte cell ratio, heart disease risk as indicated
by the lymphocyte to monocyte cell ratio, CD38-positive blood cell
counts or percentages, hair color, IL-7 levels, IL-21 levels, the
CD4/CD8 cell ratio, naive CD4 and/or CD8 cell numbers or
percentages, total CD4 and/or CD8 T cell numbers or percentages,
bone marrow density, thymic fat-free fraction, glomerular
filtration, and epigenetic age, as well as to reduce or prevent
GH-induced of GH releaser-induced hyperinsulinemia. The method may
consist of administering three separate agents or agent classes
(the GH and/or GH releaser; DHEA; and metformin) simultaneously or
within 2 hours of one another, or it may consist of administering
GH and/or a GH releaser simultaneously with or within two hours of
the oral administration of a unified companion product composition
containing DHEA in combination with metformin.
[0033] Suitable Medication Compositions
[0034] The utility of GH for the invention as reduced to practice
is proven beyond doubt by the Examples described below. The purpose
of administering GH is to increase circulating levels of both GH
and IGF-1, which then modulate appropriate biological targets to
produce the intended therapeutic effects. However, GH is costly,
and alternative means are available for elevating circulating GH
and IGF-1 so as to modulate the same biological targets as are
modulated by GH and IGF1 and thereby to achieve the same biological
effect as is achieved by GH injection. Therefore, any method,
composition, or use of agents to manufacture a pharmaceutical
dosage form that raises blood concentrations of GH and IGF-1 so as
to produce the same therapeutic effect as GH injection within the
practice of the present invention is an acceptable equivalent
method, composition, or use to GH injection, GH, or GH use,
respectively, for the purposes of the present invention.
[0035] Within the purposes of the present invention, "a GH
releaser" or "GH releaser" is understood to mean either a single
molecular entity (including complexes such as salts) or a
combination of molecular entities whose administration results in
an increase in circulating blood levels of GH and IGF-1 such that
the resulting blood concentrations of GH and IGF-1 fall within the
range of the concentrations that are reached (in individuals
capable of increasing IGF-1 levels in response to GH injection)
after GH is injected for the purposes of the present invention.
However, it is not necessary to measure blood concentrations of GH
for the purpose of determining the effectiveness of a GH releaser,
because suitable increases in blood GH levels can be inferred from
suitable increases in blood IGF-1 levels, and blood IGF-1 levels
are conveniently measured, whereas GH levels are often awkward and
costly to measure. The prior art has verified the release of GH by
GH releasers, and there is no need to duplicate that verification
in individuals. As long as the IGF-1 response to GH releaser
administration is measured and is found to be satisfactory, use of
the GH releaser is appropriate. For those individuals for whom the
administration of a GH releaser does not result in an adequate
increase in IGF-1, the use of GH is preferred over the use of a GH
releaser for the purposes of the present invention. For purposes of
evaluating the suitability of a GH releaser for use in this
invention, a fold change in IGF-1 level of at least 1.2 fold, or a
final IGF-1 concentration of at least 170 ng/ml, are indicative of
at least the potential for an adequate response.
[0036] GH releasers are well known to those of skill in the art.
Examples include but are not limited to: sermorelin, ipamorelin,
ghrelin, GHRH, and MK-0677.
[0037] In each case, the dose of GH releaser to be administered is
equal to the dose required to optimize the CD4/CD8 cell ratio,
which will be specific to each individual, using the dosing method
described below.
[0038] In the prior art, GH releasers have been used as
alternatives to the use of GH. However, a useful variation of part
of our pharmaceutical composition is a combination of GH and a GH
releaser. GH is ideally administered at bedtime, so as to simulate
the normal diurnal elevation of IGF-1 that occurs during sleep,
when the largest release of GH normally takes place. However,
injection of recombinant GH (the preferred form of GH to be used in
the present invention) may blunt the natural release of GH by the
pituitary, thus both disturbing normal GH physiology and resulting
in a need for a higher dose of GH than would be the case if natural
GH release occurred. This problem can be overcome by combining GH
and a GH releaser into a unified product composition using methods
known in the art, or co-administering both GH and GH releaser as a
virtual unified product, which can be marketed as one product. This
approach and composition will be valuable when GH injection is
generally preferred over the use of a GH releaser, but it is
desired to reduce the cost of GH injection, and when the use of a
GH releaser alone is able to raise IGF-1 levels but is insufficient
to optimize the CD4/CD8 cell ratio. The approach will also be
appealing to those who wish to combine the benefits of GH with the
theoretical safety advantages of GH releasers.
[0039] In combinations of GH and GH releaser, the dose of GH will
generally be reduced by 10-50% compared to non-use of a GH
releaser, and the dose of GH releaser will generally be in the
range of 30-100% the dose that would be administered without GH.
Typically, GH and GH releaser preparations consist of a
standardized amount of freeze-dried powder that is reconstituted to
a liquid state prior to injection. A convenient unified dosage form
can contain 50% as much GH per vial of powder as is normally
present and 75% as much GH releaser as is normally present, with
total delivered dose per injection being determined by the volume
injected as required on an individualized basis.
[0040] The inclusion of both DHEA and metformin within the
invention was discovered to be mandatory for optimum control of
GH-induced hyperinsulinemia. Even though each agent was beneficial
for suppressing hyperinsulinemia, neither agent alone was
sufficient, and even in combination, it was necessary to employ the
maximum permissible doses of each within the limits set by the
trial design. Sulfonylureas and meglitinides, which increase
insulin secretion, are inappropriate treatments for
hyperinsulinemia.
[0041] DHEA and metformin can easily be combined into a single
dosage form or composition because both are solids and will be
chemically stable when combined. A unified composition of DHEA and
metformin is advantageous for simplifying treatment, improving
patient compliance, ensuring correct dosage administration, and
adapting both DHEA and metformin pharmacokinetics to the purposes
of the present invention. In particular, a significant deficiency
of metformin and of lower doses of DHEA for the suppression of
GH-induced hyperinsulinemia is the fact that the half-lives of
these agents in the bloodstream are shorter than the expected
duration of hyperinsulinemia. By incorporating DHEA and metformin
into a timed-release formulation, which is easily done using
technologies known to those of skill in the art, the
antihyperinsulinemic effect of this combination of agents can be
tailored to match the duration of the hyperinsulinemic effect of GH
or a GH releaser. In general, release over 9-15 hours is desirable
to either completely suppress hyperinsulinemia or enable
hyperinsulinemia to be controlled during sleep so that a second
dose of DHEA plus metformin can be administered in the morning to
continue insulin suppression.
[0042] As described below, useful initial doses of DHEA and
metformin are 75 mg and 850 mg, respectively, which may be combined
into one dosage form containing these quantities. Ingesting two
such tablets will deliver 150 mg of DHEA and 1700 mg of metformin,
which are both useful doses during high to intermediate dosing with
GH/GH releaser. At the highest doses of GH/GH releaser, three
tablets comprising 225 mg of DHEA and 2550 mg of metformin can be
ingested, either simultaneously or in divided doses taken within
2-4 hours of GH administration, including one tablet with dinner
and two tablets at bedtime along with GH/GH releaser. This dosage
form will be advantageous with or without timed release
formulations; 225 mg of DHEA is projected to sustain elevated DHEA
levels for over 9 hours, whereas the half-life of metformin is
shorter and may justify selective time release of this agent. Of
course, other variations are practicable within the invention,
including a tablet containing only 33 or 50 mg of DHEA and 850 mg
of metformin for men with initial PSA levels between 3 and 4 at the
onset of the trial (these men can begin with 50 mg/850 mg and
switch to two or three 33 mg/850 mg tablets as insulin suppression
needs increase, so as to limit ultimate DHEA intake to 99 mg/dose),
and a women's tablet that contains only 17 or 33 mg of DHEA and 850
mg of metformin, to limit the highest intake to 51 or 99 mg,
respectively, when three tablets are consumed. Women can and should
initiate treatment with the men's 50 mg DHEA plus 850 mg metformin
tablet, and then switch to one of the other women's tablets when
the number of tablets needed to suppress insulin levels increases
to two or three.
[0043] The above formulations are designed particularly to combat
nocturnal hyperinsulinemia and enable the user to awake with a
normal insulin level despite taking antihyperinsulinemic therapy
only once, prior to sleeping. However, they will be useful as well
for daytime GH therapy, combining greater convenience with better
insulin control overall. In fact, these companion formulations can
be used by individuals who are taking metformin for type 2
diabetes, who may benefit from the inclusion of DHEA and timed
release of metformin, without thymus regeneration or aging reversal
therapy.
[0044] The inventors believe that the combination of GH or a GH
releaser with DHEA and metformin creates an invention that is "more
than the sum of its parts." For reasons that are not completely
clear, the combination of these specific agents has beneficial
effects that are otherwise not available. For example, as noted
above, GH alone is generally expected to accelerate epigenetic
aging rather than to reverse it, metformin use was not shown to
either slow or reverse epigenetic aging in women [35], and there is
no evidence that DHEA alone can reverse epigenetic aging, but the
combination of agents comprising the present invention quite
clearly does have this profound and unprecedented effect. As
another example, one individual has reported that DHEA caused
immediate and significant prostatic hypertrophy when used either
alone or in combination with metformin, but when it was used in
combination with both metformin and GH, prostatic hypertrophy was,
surprisingly, actually reversed (made significantly less than prior
to DHEA administration), and sexual function was also improved.
Therefore, we do not believe that the totality of the effects of
our invention would be obvious to one of ordinary skill in the art
based on prior art knowledge. Accordingly, our results, methods,
and medication compositions and combinations enable beneficial new
treatments to improve human health and enable beneficial new drug
indications.
[0045] Medication Doses and Medication Dose Administration
[0046] Best Mode GH/GH releaser Administration Method. The initial
dose of GH for men is preferably in the range of 0.01-0.02 mg/kg,
to enable pre-adaptation of the body to GH without side effects,
preferably for 1-6 weeks. The initial dose of GH releaser is chosen
to produce the same effect on IGF-1 levels as 0.01-0.02 mg/kg GH,
as determined from prior art knowledge, and is also maintained for
1-6 weeks when a GH releaser is used in place of or in addition to
GH. Postmenopausal women should be started on the same dose regimen
whether or not they are taking estrogen replacement hormones (HRT).
Women on HRT will experience lower increases in IGF-1, but lower
increases in IGF-1 will enable more thorough evaluation of safety
prior to increasing doses for thymus regeneration/aging reversal.
Women should be carefully evaluated for breast cancer risk prior to
enrolling in thymus regeneration/aging reversal treatment,
including genetic testing for alleles that favor breast cancer
development.
[0047] After the initial adaptation phase, the dose of GH, GH
releaser, or GH plus GH releaser is increased so as to maximize the
CD4 to CD8 cell ratio, as measured by commonly available blood
testing services, over about the next 60 days in both men and
women. Typically, a target CD4/CD8 ratio of 120.+-.10% of baseline
is considered satisfactory for 50-65 year-old men and women,
regardless of the initial absolute CD4/CD8 ratio, and regardless of
whether the ratio is increased by a decrease in CD8 cell counts or
percentages or by an increase in CD4 cell counts or percentages
(both ways of computing the CD4/CD8 cell ratio give similar results
and are acceptable for purposes of the invention).
[0048] The preferred GH/GH releaser dosing frequency should be 4-7
times a week. Side effects should be controlled by reducing dosing
frequency first and then, if that is insufficient, by dose
reductions. A dosing frequency as low as 3 times a week can be
effective for some patients.
[0049] We find that a maximum CD4/CD8 cell ratio is achieved in
different individuals over a broad range of absolute IGF-1
concentrations and IGF-1 fold changes. The prior art method of
increasing IGF-1 levels or inducing IGF-1 fold changes to either an
arbitrary extent or as much as possible within upper physiological
limits was found to be counterproductive, resulting in eventual
decreases in the CD4/CD8 cell ratio. We also found wide variations
in IGF-1 concentrations in response to a specific dose of GH, and
essentially no correlation between CD4/CD8 cell ratio and IGF-1
concentration. Therefore, the optimum dosing strategy is to
optimize CD4/CD8 cell ratio by either increasing or decreasing the
GH/GH releaser dose as may be necessary as indicated by how the
ratio changes with dose. This dose-response relationship may also
change over time, so monitoring once every 1-3 months is
recommended. Thus, medical supervision is necessary for achieving
optimal results.
[0050] The strategy of dosing based on the CD4/CD8 ratio is unique,
and is the first non-arbitrary method of GH/GH releaser
administration. This method was inferred a posteriori based on the
unprecedented observation that with the prior art method, the
CD4/CD8 ratio tended to peak after different treatment times in
different individuals, and then further decline, as described in
detail below.
[0051] Because food and alcohol may inhibit natural HGH release
from the pituitary, the effectiveness of GH in the present
invention should be maximized by not drinking alcoholic or sugary
beverages or consuming significant quantities of food within 2-4
hours of injecting GH.
[0052] Best Mode DHEA Administration Method. DHEA was not found to
either raise testosterone levels (at doses up to 200 mg) or induce
benign prostatic hypertrophy in the presence of GH or GH plus
metformin in our trial. The best mode use is to administer DHEA
within one or two hours, and ideally simultaneously, with the
administration of GH. A useful initial oral dose of DHEA for most
men, once GH treatment begins, is 75 mg. Men with PSA levels
between 3 and 4 should restrict DHEA to 50 mg initially, and raise
DHEA only if benign prostatic hypertrophy and/or PSA elevation is
not encountered. Men with PSA levels above 4 should not undergo
thymus regeneration/age reversal therapy unless PSA elevation is
caused by established prostatitis or until additional information
becomes available establishing the safety of treatment for such
men. We believe that for most men, 300 mg of DHEA should be safe,
but we recommend limiting DHEA intake to 225 mg until more safety
information becomes available.
[0053] Women can safely take 50 mg of DHEA, and in the best mode,
this is the preferred initial dose unless specific issues arise for
particular women. Out of general caution, we recommend limiting the
intake of DHEA to 100 mg for women. This can be achieved using the
dosage forms described above, which ensure limitation of DHEA to 51
or 99 mg even when antihyperinsulinemic therapy is maximized.
[0054] Best Mode Metformin Administration Method.
[0055] A useful initial dose of metformin, which should be given
upon initial administration of GH, is 850 mg. If necessary to
prevent gastric distress, this dose can be divided into two doses
taken as close together in time as gastric distress will permit.
Most individuals do not have difficulty taking this or higher doses
of metformin. Metformin, like DHEA, can be taken either as part of
a virtual composition or as part of a unified product composition
containing both DHEA and metformin, as detailed above.
[0056] As for GH/GH releaser administration, the intake of
metformin and DHEA should gradually increase over about the first
60 days of therapy to adjust to the continuously changing degree of
insulin resistance induced by the GH/GH releaser. Thereafter, an
additional, slower increase or decrease may be required, as GH/GH
releaser dose is fine-tuned and the body adjusts to all three
medications. The metformin dose ranges for men and women are the
same. However, if women experience a different hyperinsulinemic
effect than men, or a different antihyperinsulinemic effect of DHEA
and metformin, dose adjustments can easily be made as
necessary.
[0057] The metformin dose ranges described here differ
significantly from ranges recognized in the prior art. The maximum
accepted single dose of metformin is 850-1200 mg, and doses above
850 mg may cause an upset stomach in some users. However, in our
experience, and as newly disclosed herein, 850-1200 mg of metformin
is very insufficient to control hyperinsulinemia induced by GH in,
as measured the morning after a GH dose (typically, at 8-10 am),
even when DHEA is co-administered. We were able to use higher doses
with minimal to no difficulty by devising the following dosing
methods.
[0058] First, 500 mg of metformin can be given with dinner, and
another 1000 mg can be co-administered with HGH and DHEA, achieving
a total dose of 1500 mg. This regimen was universally well
tolerated. Second, taking 1500 or 2000 mg of metformin in one dose
together with GH at bedtime was also well tolerated, perhaps
because the onset of sleep relieves feelings of gastric discomfort.
Third, taking 1500 mg at dinner and 1000 mg with DHEA and HGH at
bedtime was also well tolerated, enabling us to attain a dose of
2500 mg. In these methods, "dinner" need not be taken literally,
the essence of the concept being to essentially administer a large
virtual dose by combining two smaller doses that are administered
within an effective time span, which may be 1-5 hours in duration,
but preferably 1-2 hours in duration, to reduce side effects such
as gastric distress while still enabling increased control of
hyperinsulinemia.
[0059] Essentially, we learned that we could compensate for the
short half-life of metformin in the bloodstream (.about.2-3 hours)
by using quantities beyond normal dosing limits to prolong its
effectiveness, and discovered that this was acceptable in all
cases, perhaps in part because we administered GH at night to
simulate the normal diurnal peak in GH that takes place shortly
after the onset of sleep. However, the same goals can be achieved
even more effectively by using the timed dose release preparation
described herein, which will deliver metformin or metformin and
DHEA over a longer time span, both reducing gastric distress and
achieving longer-lasting protection from hyperinsulinemia. In
addition, this preparation can also if desired be taken during the
day without distress due to slower release of the metformin.
[0060] Short Term Thymus Regeneration and Aging Reversal is
Sufficient
[0061] A unique feature of our treatment is that it need not and
should not be implemented for the life of the patient in order to
achieve life-long benefits. Once thymus regeneration has been
established and new T cells have been produced and released into
the circulation, they may persist for decades even though the
thymus will re-involute following the termination of treatment. In
addition, aging reversal, once shown to be long-lasting, might only
need to be repeated once every few years, or less frequently. This
feature of the present invention is advantageous for reasons of
both safety and cost, and as further improvements of our invention
are made, the duration of benefit may become longer still, and the
duration of required treatment may become shorter. In the present
best mode practice of the invention, we believe that the optimum
treatment time is 0.5-1.5 years, and perhaps 0.75-1.25 years.
EXAMPLES
[0062] Nine normal, putatively healthy 50-65 year-old male
volunteers with normal age-related thymic involution were enrolled
in and completed a clinical study performed under an IND from the
US Food and Drug Administration and separate supervision from a
California Institutional Review Board. All aspects of the study
also complied with the oversight requirements and standards of
multiple institutions at Stanford University. The TRIIM trial
(standing for Thymus Regeneration, Immunorestoration, and Insulin
Mitigation) treatment period was limited to 12 months. Exclusion
criteria included GH use in the prior 10 years, carpal tunnel
syndrome, malignancies or high risk of malignancy, BMI greater than
30, PSA above the age-adjusted range, symptomatic prostatic
hypertrophy, unstable metabolic disorders, unstable cardiovascular
disorders, elevated levels of inflammatory markers, alcoholism,
allergy to study medications, cognitive impairment, abnormal
metabolic or hormonal results, existing type 1 or type 2 diabetes,
or other unstable medical conditions. Informed consent was obtained
from all patients and was collected using IRB-approved informed
consent documents and procedures. The study was conducted
consistently with the Declaration of Helsinki, Protection of Human
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56),
and Obligations of Clinical Investigators (21 CFR 312).
[0063] Data variability was minimized and controlled by using each
volunteer as his own control, and by standardizing the time and day
of blood sampling. Blood was generally collected between 7 AM and
10 AM to avoid the effects of circadian and other temporal
influences. In addition, patients standardized their pre-testing
evening meal, used consistent testing sites and methods, and were
redundantly tested between pre-established time points in some
cases. All volunteers were asked to take supplements of 3000 IU
vitamin D.sub.3 and 50 mg of elemental zinc daily. Further,
volunteers were instructed not to consume food or alcohol within 4
hours of medication administration.
[0064] The initial dose of GH was 0.015 mg/kg, injected
subcutaneously into superficial abdominal fat using a provided
"pen" injector designed for this purpose. GH doses were varied over
the time course described above so as to maximize IGF1, and were
not adjusted for any changes in body weight.
[0065] Insulin mitigation in the trial was staged to enable the
effects first of DHEA and then of DHEA plus metformin to be
evaluated. The course of dose adjustment of DHEA and metformin in
the trial were as described above.
[0066] The following unexpected and remarkably beneficial new
discoveries were made as a result of the TRIIM trial.
Example 1
[0067] As shown in FIG. 1, as the trial progressed and GH doses
increased, there was a sustained trend for high-sensitivity CRP
(hsCRP), a marker of systemic inflammation, to decrease. By 9-12
months, the decrease was about 40.+-.10%, which is substantial, and
the decline in hsCRP at 9-12 months was statistically significant
compared to baseline (p<0.001). Normally, hsCRP would be
expected to rise or stay the same over a one-year period, but with
the treatment and medications of the invention, this normal
age-related trend was reversed, despite attempted reactivation of
the aging immune system. This contradicts the prior art concern
that immune stimulation must exacerbate inflammation, and indicates
that it is possible to simultaneously increase immune competence
(see below) and decrease inflammation.
Example 2
[0068] FIG. 2 provides evidence that the medications of the
invention surprisingly and rapidly (within 1 month) reverse the
normal age-related increase in prostate cancer risk based on
reduced levels of prostate-specific antigen (PSA, which rises with
risk), increased percentages of free (unbound) PSA (with declines
with increasing risk), and the ratio of PSA to free PSA, which was
devised as an overall index of risk. Throughout most of the trial,
relative risk is reduced by about 30%, and at 12 months, the risk
factor decrease of nearly 40% was significant at the p<0.001
level. The increase in PSA, decrease in percent free PSA, and spike
in putative overall risk at 6 months was due to results for three
men. Given the immediate return to normal values after this time
point (in the worst case, PSA was re-checked one week after the
aberrant result, and was found to have returned to baseline levels,
and in no case did the PSA level rise to 4 or above), the spike was
not due to prostate cancer, and is believed to have been due to
sexual activity too close to the time of blood collection.
[0069] The results of FIG. 2 are remarkable because they show a
reduction in prostate cancer risk by a treatment that induces
greatly increased IGF-1 levels, which have been considered a risk
factor for prostate cancer, coupled with the use of an androgenic
steroid. This effect on cancer risk is entirely unpredictable over
the prior art and remains unexplained. Furthermore, the trend is
strong enough to be clearly visible even in a group of only 9
rather heterogeneous aging men. Not visible in this figure is the
fact that this trend applied without regard to baseline prostate
cancer risk, men with PSA levels between 3 and 4 at the onset of
the trial benefitting by the same proportion as men with PSA levels
of 2 and below.
Example 3
[0070] FIG. 3 shows the ratio of circulating CD38 positive
monocytes to total lymphocytes over the 12 months of the TRIIM
trial and for another 6 months after discontinuing treatment. There
is more than a 33% decline in the monocyte to lymphocyte ratio
(MLR), which is quite significant, both biologically and
statistically (p=0.00055), and this decline persists after
discontinuing treatment. This is to be understood in the light of
the fact that CD38 is the enzyme whose age-related increase in
expression drives the cardinal age-related loss of NAD [8], which
in turn drives deep and widespread aspects of mammalian aging [15].
An increased MLR also strongly correlates with the age-related
increase in risk of both cancer [27] and cardiovascular disease
[22]. Cancer and cardiovascular disease are the two leading killers
of aging humans, and reduced risk from these two diseases of aging
further suggests a general reversal of aging processes. The MLR was
determined from CyTOF analysis of TRIIM PBMC samples that were
stored and analyzed at Stanford's Human Immune Monitoring
Center.
Example 4
[0071] FIG. 4 shows the relationship between thymic fat-free
fraction (TFFF; see below) and the lymphocyte to monocyte cell
ratio (LMR). The statistical significance of the correlation is at
the p=0.0019 level, and links the improvement in LMR to the
improvement in putative thymic functional mass. In fact, when
variance explained by changes in TFFF are factored out of variance
in the LMR, no change in LMR survives, suggesting that changes in
the LMR are in fact caused by improvements in thymic function.
Example 5
[0072] To our surprise, three of our trial volunteers (33%)
reported to us that their wives and friends had noticed darkening
of their hair. FIG. 5 provides evidence that the invention
surprisingly reverses the aging of hair follicles, based on three
before-and-after comparisons showing one volunteer's hair a few
months before treatment and at the end of treatment. This result is
all the more remarkable considering that hair whitening is caused
by the death of follicular melanocyte stem cells, suggesting
restoration of stem cells by the invention.
[0073] These observations were completely unanticipated. This
phenomenon is suggestive of a broad "anti-aging" effect, and has
not been reported to our knowledge after use of any of the
individual agents of the present invention (in this case, GH, DHEA,
and metformin) when they are not combined with one another as
required by the present invention, and this effect of the
combination is unpredictable from the properties of the uncombined
agents. The phenomenon adds further market appeal to the treatment,
manufacturing process, medication combination, and compositions of
the present invention.
Example 6
[0074] FIG. 6 provides evidence that the invention surprisingly
restores thymotrophic hormones in a subset of TRIIM trial
volunteers, based on correlated increases in both IL-7 and IL-21
(FGF-21) in these men. IL-7 is a hormone whose downregulation in
youth has been associated with the onset of thymic involution, and
restoration of which has been proposed, but not achieved, for
inducing thymic regeneration [5]. IL-21 has been shown to
regenerate the aged thymus in rodents when excessively
over-expressed to a level that may or may not be feasible or
desirable in humans [2, 47], and is a theoretical alternative
pathway to thymus regeneration. We asked whether part of the
mechanism of action of our invention was induction of IL-7 and/or
IL-21, i.e., stimulation by our medication combination of
endogenous thymic regeneration pathways. FIG. 6 indicates that the
answer to the question is positive, and demonstrates a heretofore
unknown and safe method for increasing IL-7 and IL-21 in humans.
Once again, reactivation of pathways found in youth provides
additional evidence for an overall aging reversal effect of our
combination of medications.
Example 7
[0075] FIG. 7 reveals a heretofore unknown phenomenon, i.e., that
the CD4/CD8 cell ratio peaks in the face of a constant or an
increasing dose of GH or rise in IGF-1, and thereafter declines.
Different men show a peak in CD4/CD8 ratio at different times
(here, 3, 6-9, and 12 months; one volunteer failed to respond at
any time). The decline of CD4/CD8 cell ratio with aging is a
classical indication of the "immune risk phenotype" or
immunosenescence, and appears to occur with or without chronic
viral exposure [24] and has been a strong predictor of the
short-term risk of death [37]. Our results therefore indicate that
prior art methods of regenerating the thymus require improvement.
Without knowledge of the phenomenology of FIG. 7, it was impossible
to optimize GH therapy during the TRIIM trial, and in fact, the
phenomenon was not understood until after the end of the trial, but
we can now infer that the GH dose should stop increasing, and
should even begin to decrease, when the CD4/CD8 cell ratio is
observed to peak, so that the peak can be sustained. Although the
considerable successes of the TRIIM trial were achieved without the
advantage of the teachings of FIG. 7, adjusting treatment according
to the findings of FIG. 7, as described herein, should produce
still stronger benefits.
Example 8
[0076] FIG. 8 provides detailed information on the improvement in
functional thymic mass achieved by the TRIIM trial protocol and
medications, as inferred from a reduction in the thymic fat
percentage (TFFF=thymic fat-free fraction=100 minus the percentage
of thymic mass represented by fat, where the thymic fat fraction
was computed using an algorithm that has been shown to be of higher
accuracy than standard histopathological assessment by biopsy
[21]). Two basic phenomena are seen. First, for most men, there was
a steady replacement of thymic fat with putative thymic functional
mass from 0 to 9 months of treatment. In some cases, this
improvement continued, whereas in others, it appeared to regress
slightly from 9 to 12 months, akin to the peaking of the CD4/CD8
cell ratio described in FIG. 7, and perhaps originating from the
same preventable cause. Second, two exceptional individuals showed
a different pattern: their baseline TFFF was abnormally high and
showed little improvement over time. These findings are further
referred to in conjunction with the discussion of FIG. 9 below.
Example 9
[0077] FIG. 9 provides a glimpse of some of the evidence that the
invention is able to improve T cell populations in at least a
subset of aging men and that the subset of men who benefit can be
predicted prior to treatment and is closely related to changes seen
in the thymus. As can be seen, the relative improvement of TFFF
depends on basal TFFF: the higher the TFFF at baseline, the less
room there is for improvement. Similarly, the improvement of naive
CD8 cell counts also depends on how high the counts are at
baseline: volunteers with high naive CD8 cell numbers at baseline
have less need for improvement, and show less improvement, but
despite lack of improvement, absolute counts remain good. Also,
like TFFF, naive CD8 cell counts are sometimes lower at 12 months
than at 9 months in some cases, whereas volunteers with lower naive
CD8 cell counts at baseline, who have a stronger need for improved
counts, show continuing improvement between 9 and 12 months. These
results represent only a partial analysis of the TRIIM data;
additional analysis is likely to show additional evidence of
benefit. Note that the lower right panel shows that TFFF and naive
CD8 cells don't correlate well at baseline; therefore, changes in
TFFF and naive CD8 cells can only be correlated by showing the same
trends in both, as demonstrated here.
[0078] In addition to the data shown here, there is a way to infer
naive CD8 cell counts from epigenetic clock data, which may be more
accurate than relying on a relatively small number of frozen-thawed
cell samples. On the basis of such data, the p value for an overall
increase in naive CD8 cell counts was found to be p=0.0017. A
similar analysis for naive CD4 cells fell just short of statistical
significance, but subgroup analysis of the kind shown for naive CD8
cells in FIG. 9, now underway, may reveal subsets of volunteers
whose improvements in naive CD4 cells are clear.
[0079] The fact that thymic structural improvement, the CD4/CD8
cell ratio, and naive CD8 T cells all show signs of improvement to
a certain point followed by a small reversion toward baseline
supports the significance of adjusting treatment based on the
CD4/CD8 cell ratio so as to prevent overdosing and desensitization
of the thymus.
[0080] Meanwhile, the observations of FIG. 9 provide valuable
diagnostic criteria (TFFF and naive CD8 cell counts) by which
patients wishing to consider thymus regeneration and aging reversal
treatment can be evaluated prior to treatment to determine their
likelihood of experiencing a positive response.
[0081] Finally, the restoration of naive CD8 and perhaps naive CD4
T cells represents yet one more example of processes that are the
opposite of normal age-related trends.
Example 10
[0082] We observed that the treatment medications and methods were
able to reverse age-related fatty infiltration of the bone marrow,
based on the same analytical method used to determine an
improvement in TFFF. The p value for this change was
9.5.times.10.sup.-12. Bone marrow function in aging is important
for many reasons, but one important reason is that the bone marrow
supplies progenitor T cells to the thymus, where they mature into
competent T cells in youth. Successful immunorestoration in the
elderly requires appreciable bone marrow function, and the changes
observed from MRI investigation of bone marrow indicate that the
medications of the present invention have effects on bone marrow
consistent with this requirement. This change is one more change
that is contrary to the direction of normal aging trends.
Example 11
[0083] FIG. 10 shows that the medications and treatments of the
present invention result in increased glomerular filtration rates
over the course of the 12 months of treatment and beyond, reaching
statistical significance at 9 months, 12 months and overall out to
18 months. "eGFR" is "estimated GFR" and is calculated based on
age, sex, race, and serum creatinine levels. Normally, renal
function declines with aging. Here is another example of the
functional reversal of a normal age-related trend.
Example 12
[0084] FIG. 11 demonstrates the first direct evidence for a global
reversal of human aging. Using an epigenetic clock licensed by Zymo
Research [20], the longitudinal epigenetic age of TRIIM trial
volunteers was calculated at months 0, 9, and 12. At baseline
(month 0), the mean epigenetic age of the volunteers was about 0.75
years older than their chronological ages. By 9 months, there was a
gain of about 0.8 years, indicating rejuvenation back to a
biological age appropriate for the volunteers' mean chronological
age. However, three months later, the mean epigenetic age had
declined to 1.5 years younger than the volunteers' mean
chronological age. In total, net rejuvenation after 1 year of
treatment was about 2.25 years. But since 1 year of treatment would
have normally entailed one additional year of aging, the net gain
was actually 3.25 years compared to no treatment. The p value for
this change was 0.0059. In general, epigenetic clocks of this kind
can determine biological age more accurately than biological age
can be estimated from chronological age.
Example 13
[0085] FIG. 12 demonstrates that the invention can successfully
suppress GH-induced hyperinsulinemia despite the increasing GH
doses described in FIG. 1. Here, for context, insulin blood levels
are expressed as a fraction of the distance from the bottom of the
normal range to the top of the normal range. Although insulin
control was not perfect, the final increase in insulin at trial end
was acceptable based on volunteers averaging about one fifth of the
upper limit for insulin. Note the rise in insulin early on, as
lower doses of GH were given without administration of DHEA or
metformin, followed by declining insulin levels as
antihyperinsulinemic therapy was begun. Insulin and the normal
insulin range were as reported by Quest Diagnostics.
SUMMARY
[0086] The present invention provides for the first time medication
combinations, compositions, doses, dosage regimens, and other
methods that have demonstrable and objective benefits for the
treatment of immunosenescence and many fundamental aspects of aging
in human patients, and for further improvements that are now
enabled by the present disclosures.
[0087] Additional ways to describe the invention include the
following.
[0088] 1. A method whereby the co-administration of human growth
hormone and/or one or more human growth hormone releasing agents,
DHEA, and metformin to humans results in the reversal of
age-related health risk factors other than thymic involution.
[0089] 2. The method above ("the method") wherein the dose of human
growth hormone or growth hormone releasing agents is adjusted in
response to changes in the CD4 to CD8 T cell ratio so as to prevent
the CD4 to CD8 T cell ratio from declining due to over- or
under-administration of human growth hormone or growth hormone
releasing agents.
[0090] 3. The method, wherein one age-related health risk factor
that improves is the age-related decrease of estimated or directly
measured glomerular filtration rate.
[0091] 4. The method, wherein one age-related health risk factor
that improves is the age-related increase in the blood level of
prostate-specific antigen (or PSA) and/or the age-related decrease
in the percent of free PSA.
[0092] 5. The method, wherein one age-related health risk factor
that improves is systemic inflammation, where the improvement is
indicated by a decrease in high-sensitivity C-reactive protein
(hsCRP) blood levels.
[0093] 6. The method, wherein one age-related health risk factor
that improves is the risk of cardiovascular disease, where the
improvement is indicated by an increased lymphocyte to monocyte
ratio.
[0094] 7. The method, wherein one age-related health risk factor
that improves is the risk of cancer, where the improvement is
indicated by an increased lymphocyte to monocyte ratio.
[0095] 8. The method, wherein one age-related health risk factor
that improves is the age-related increase in CD38 levels, where the
improvement is indicated by a decrease in CD38 positive
monocytes.
[0096] 9. The method, wherein said co-administration of human
growth hormone and/or one or more human growth hormone releasing
agents, DHEA, and metformin to humans also results in increased
hair pigmentation.
[0097] 10. The method, wherein said co-administration of human
growth hormone and/or one or more human growth hormone releasing
agents, DHEA, and metformin to humans also results in increased
blood levels of FGF21/IL21 and/or IL7.
[0098] 11. The method, wherein the dose of DHEA is 17-300 mg.
[0099] 12. The method, wherein the dose of metformin is 500 to 2500
mg.
[0100] 13. The method, wherein metformin or metformin and DHEA are
provided in a unified composition.
[0101] 14. The method, wherein said unified composition of
metformin and DHEA is provided in a timed-release dosage form for
better matching the half-lives of DHEA and/or particularly
metformin to the duration of the hyperinsulinemic effect of GH, GH
releaser, or GH plus GH releaser.
[0102] 15. The method, wherein said human growth hormone and/or one
or more human growth hormone releasing agents are combined into a
unified product composition.
[0103] As noted above, a major mode of biological action within the
invention is elevation of IGF-1, which may be accomplished by any
IGF-1 elevating agent, including the anabolic agent IGF-1 itself or
a combination of IGF-1 and IGFBP-3. In addition, other
insulin-mitigating agents besides DHEA and metformin may have
utility in the invention, including as weak and secondary
antihyperinsulinemic agents, such as cinnamon preparations,
chromium picolinate, and other forms known in the art. The best
mode reduction of the invention as described here is intended to be
descriptive but not limiting, and may affect other critical
endpoints of aging in addition to those described herein.
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